• Je něco špatně v tomto záznamu ?

mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma

W. Xu, P. Berning, T. Erdmann, M. Grau, N. Bettazová, M. Zapukhlyak, F. Frontzek, C. Kosnopfel, P. Lenz, M. Grondine, B. Willis, JT. Lynch, P. Klener, S. Hailfinger, ST. Barry, G. Lenz

. 2023 ; 37 (1) : 178-189. [pub] 20221109

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc23004782
E-zdroje Online Plný text

NLK ProQuest Central od 2000-01-01 do Před 1 rokem
Open Access Digital Library od 1997-01-01
Nursing & Allied Health Database (ProQuest) od 2000-01-01 do Před 1 rokem
Health & Medicine (ProQuest) od 2000-01-01 do Před 1 rokem
Public Health Database (ProQuest) od 2000-01-01 do Před 1 rokem

Odkazy

PubMed 36352190
DOI 10.1038/s41375-022-01749-0
Knihovny.cz E-zdroje

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc23004782
003      
CZ-PrNML
005      
20230425171721.0
007      
ta
008      
230418s2023 enk f 000 0|eng||
009      
AR
024    7_
$a 10.1038/s41375-022-01749-0 $2 doi
035    __
$a (PubMed)36352190
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a enk
100    1_
$a Xu, Wendan $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
245    10
$a mTOR inhibition amplifies the anti-lymphoma effect of PI3Kβ/δ blockage in diffuse large B-cell lymphoma / $c W. Xu, P. Berning, T. Erdmann, M. Grau, N. Bettazová, M. Zapukhlyak, F. Frontzek, C. Kosnopfel, P. Lenz, M. Grondine, B. Willis, JT. Lynch, P. Klener, S. Hailfinger, ST. Barry, G. Lenz
520    9_
$a Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease that exhibits constitutive activation of phosphoinositide 3-kinase (PI3K) driven by chronic B-cell receptor signaling or PTEN deficiency. Since pan-PI3K inhibitors cause severe side effects, we investigated the anti-lymphoma efficacy of the specific PI3Kβ/δ inhibitor AZD8186. We identified a subset of DLBCL models within activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL that were sensitive to AZD8186 treatment. On the molecular level, PI3Kβ/δ inhibition decreased the pro-survival NF-κB and AP-1 activity or led to downregulation of the oncogenic transcription factor MYC. In AZD8186-resistant models, we detected a feedback activation of the PI3K/AKT/mTOR pathway following PI3Kβ/δ inhibition, which limited AZD8186 efficacy. The combined treatment with AZD8186 and the mTOR inhibitor AZD2014 overcame resistance to PI3Kβ/δ inhibition and completely prevented outgrowth of lymphoma cells in vivo in cell line- and patient-derived xenograft mouse models. Collectively, our study reveals that subsets of DLBCLs are addicted to PI3Kβ/δ signaling and thus identifies a previously unappreciated role of the PI3Kβ isoform in DLBCL survival. Furthermore, our data demonstrate that combined targeting of PI3Kβ/δ and mTOR is effective in all major DLBCL subtypes supporting the evaluation of this strategy in a clinical trial setting.
650    _2
$a lidé $7 D006801
650    _2
$a zvířata $7 D000818
650    _2
$a myši $7 D051379
650    12
$a fosfatidylinositol-3-kinasy $x metabolismus $7 D019869
650    _2
$a signální transdukce $7 D015398
650    12
$a difúzní velkobuněčný B-lymfom $x patologie $7 D016403
650    _2
$a TOR serin-threoninkinasy $x metabolismus $7 D058570
650    _2
$a nádorové buněčné linie $7 D045744
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Berning, Philipp $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
700    1_
$a Erdmann, Tabea $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
700    1_
$a Grau, Michael $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
700    1_
$a Bettazová, Nardjas $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic $u Department of Medical Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Zapukhlyak, Myroslav $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
700    1_
$a Frontzek, Fabian $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany $1 https://orcid.org/0000000317053638
700    1_
$a Kosnopfel, Corinna $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany $1 https://orcid.org/000000020910838X
700    1_
$a Lenz, Peter $u Department of Physics, University of Marburg, Marburg, Germany $u LOEWE Center for Synthetic Microbiology, Marburg, Germany
700    1_
$a Grondine, Michael $u Bioscience, Early Oncology, AstraZeneca, Boston, MA, USA
700    1_
$a Willis, Brandon $u Bioscience, Early Oncology, AstraZeneca, Boston, MA, USA
700    1_
$a Lynch, James T $u Bioscience, Early Oncology, AstraZeneca, Cambridge, UK
700    1_
$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic $u First Department of Internal Medicine - Department of Hematology, University General Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
700    1_
$a Hailfinger, Stephan $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
700    1_
$a Barry, Simon T $u Bioscience, Early Oncology, AstraZeneca, Cambridge, UK $1 https://orcid.org/0000000285110588
700    1_
$a Lenz, Georg $u Department of Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany. georg.lenz@ukmuenster.de $1 https://orcid.org/0000000247281693
773    0_
$w MED00003138 $t Leukemia $x 1476-5551 $g Roč. 37, č. 1 (2023), s. 178-189
856    41
$u https://pubmed.ncbi.nlm.nih.gov/36352190 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20230418 $b ABA008
991    __
$a 20230425171718 $b ABA008
999    __
$a ok $b bmc $g 1925084 $s 1190991
BAS    __
$a 3
BAS    __
$a PreBMC-MEDLINE
BMC    __
$a 2023 $b 37 $c 1 $d 178-189 $e 20221109 $i 1476-5551 $m Leukemia $n Leukemia $x MED00003138
LZP    __
$a Pubmed-20230418

Najít záznam

Citační ukazatele

Možnosti archivace